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Biomedical subjects

M Goebeler

Publications and source records attributed to M Goebeler.

At least 37 records · Page 2Linked to original sources
PubMed2002

[Blistering autoimmune diseases of childhood].

Autoimmune blistering skin diseases are exceedingly rare in children. In most cases, they are characterized by circulating autoantibodies directed against adhesion structures of the skin which subsequently induce blistering at the dermoepidermal junction or intraepidermally. The most frequent paediatric immunobullous disease is linear IgA dermatosis; all others such as pemphigoid, epidermolysis bullosa acquisita, dermatitis herpetiformis and pemphigus are less common than in adults. In children, mucous membranes are involved more frequently. Recent advances in the identification of the autoantigens have improved diagnostic approach and therapeutic management of blistering diseases. In most cases, treatment requires systemic immunosuppression. With respect to the chronic course of the diseases and potential complications of treatment, cooperation between dermatologists and paediatricians seems advisable.

Autoimmune Diseases↗
PubMed2002

[Spondyloarthritis].

Explore the source record for details and available documents.

Cross-Sectional Studies↗
PubMed2001

Homocysteine inhibits tumor necrosis factor-induced activation of endothelium via modulation of nuclear factor-kappa b activity.

Homocystinuria is a metabolic disorder associated with an increased incidence of vascular disease. Here, we analyzed the effects of homocysteine on endothelial cell activation that is a prerequisite for the recruitment of leukocytes to sites of evolving atherosclerotic plaques. Exposure of human umbilical vein endothelial cells to homocysteine alone did not modulate expression of the adhesion molecules E-selectin, intercellular adhesion molecule-1 and vascular cell adhesion molecule-1, and the chemokines monocyte chemotactic protein-1 and interleukin-8. In contrast, tumor necrosis factor (TNF)-induced upregulation of these molecules was almost completely inhibited by homocysteine, but not by related thiol amino acids. Using electrophoretic mobility shift and reporter gene assays, the inhibitory effect of homocysteine could be attributed to inhibition of DNA binding and transcriptional activity of NF-kappa B. TNF-induced phosphorylation and degradation of I kappa B-alpha, however, were not affected. Neither was NF-kappa B-independent activation of endothelial cells by interferon-gamma influenced by homocysteine. In summary, our data indicate that homocysteine alters the response to injury of endothelial cells which may have fundamental impacts on mechanisms of leukocyte recruitment to sites of inflammation. Our findings might refer to a novel pathway by which homocysteine is involved in vascular disorders associated with homocystinuria.

Cells, Cultured↗
PubMed2001

Activation of NF-kappa B via the Ikappa B kinase complex is both essential and sufficient for proinflammatory gene expression in primary endothelial cells.

Activation of the transcription factor NF-kappaB is necessary for full expression of tumor necrosis factor alpha (TNF-alpha)-inducible endothelial chemokines and adhesion molecules. However, a detailed analysis regarding contribution of the different NF-kappaB upstream components to endothelial activation has not been performed yet. We employed a retroviral infection approach to stably express transdominant (TD) mutants of IkappaBalpha, IkappaBbeta, or IkappaBepsilon and dominant negative (dn) versions of IkappaB kinases (IKK) 1 or 2 as well as a constitutively active version of IKK2 in human endothelial cells. TD IkappaBalpha, IkappaBbeta, and IkappaBepsilon were not degraded upon TNF-alpha exposure, and each prevented NF-kappaB activation. These TD IkappaB mutants almost completely inhibited the induction of monocyte chemoattractant protein-1, interleukin-8, intercellular adhesion molecule-1, vascular cell adhesion molecule-1, and E-selectin expression by TNF-alpha, whereas interferon-gamma-mediated up-regulation of intercellular adhesion molecule-1 and HLA-DR was not affected. Expression of dn IKK2 completely blocked TNF-alpha-induced up-regulation, whereas dn IKK1 showed a partial inhibition of expression of these molecules. Importantly, expression of constitutively active IKK2 was sufficient to drive full expression of all chemokines and adhesion molecules in the absence of cytokine. We conclude that the IKK/IkappaB/NF-kappaB pathway is crucial and sufficient for proinflammatory activation of endothelium.

Blotting, Western↗
PubMed2001

Multiple signaling pathways regulate NF-kappaB-dependent transcription of the monocyte chemoattractant protein-1 gene in primary endothelial cells.

The cytokine-induced C-C chemokine monocyte chemoattractant protein-1 (MCP-1) is an important regulator of leukocyte recruitment to sites of inflammatory challenge. Here, it is demonstrated that the widely distributed contact hapten NiCl(2), like tumor necrosis factor alpha (TNFalpha), induces monocyte-chemoattractant activity in primary human endothelial cells via induction of MCP-1. NiCl(2) rapidly activated mitogen-activated protein (MAP) kinase p38, and inhibition of p38 partially blocked NiCl(2)-induced MCP-1 messenger RNA and protein expression. Both NiCl(2)- and TNFalpha-induced MCP-1 synthesis was sensitive to D609, an inhibitor of phosphatidylcholine-dependent phospholipase C (PC-PLC). NiCl(2)-induced MCP-1 synthesis required activation of NF-kappaB since mutation of NF-kappaB-binding sites in the promoter resulted in complete loss of inducible promoter activity. Consistent with that finding, stimulation with NiCl(2) or TNFalpha activated IkappaB kinase-beta (IKKbeta), and transient transfection of dominant-negative IKKbeta strongly inhibited NiCl(2)- and TNFalpha-induced MCP-1 expression. However, D609 and the specific p38 inhibitor SB202190 did not affect NiCl(2)- and TNFalpha-induced IKKbeta activation, NF-kappaB DNA-binding activity, or transcriptional activity of a Gal4p65 fusion protein. This indicates that p38- and PC-PLC-dependent pathways directly regulate the transcriptional activity of NF-kappaB factors in the transcriptional complex. Consistent with that, inhibition of p38 blocked enhanced transcriptional activity induced by the transcriptional coactivator p300. Thus, it was concluded that at least 3 independent pathways regulate MCP-1 expression in endothelial cells. Its induction requires activation of the IKKbeta/IkappaBalpha/NF-kappaB signaling pathway, resulting in nuclear accumulation of p65 and subsequent recruitment of cofactors. Proper assembly and activity of this transcriptional complex is further modulated by the p38 MAP kinase cascade and a PC-PLC-dependent pathway.

Chemokine CCL2↗
PubMed2001

Differential and sequential expression of multiple chemokines during elicitation of allergic contact hypersensitivity.

Regulation of chemokine-mediated leukocyte migration within inflammatory tissues is a complex event that cannot be mimicked and analyzed in vitro. We therefore investigated the role of macrophage- and T-lymphocyte-specific chemoattractants involved in the positioning of immune effector cells during the elicitation phase of contact hypersensitivity, a prototype of a T-lymphocyte-mediated immune reaction. Serial sections of skin biopsies obtained from sensitized individuals at distinct time intervals after epicutaneous application of allergens were hybridized with anti-sense probes of a large panel of chemokines or immunohistologically labeled with leukocyte-specific antibodies. Multifocal expression of monocyte chemoattractant protein-1 (MCP-1) was already detected after 6 hours in basal keratinocytes clearly preceding the infiltration of monocytes and T cells. Increasing basal expression of MCP-1 and, in addition, of regulated upon activation, normal T-cell expressed and secreted (RANTES) after 12 hours was accompanied by dermal expression of MCP-1, macrophage-derived chemoattractant (MDC), and RANTES and paralleled by infiltration of mononuclear cells into dermis and epidermis. Expression of the T-lymphocyte-specific chemokines IP-10 and MIG in epidermis and dermis and of MDC, pulmonary and activation-regulated chemokine (PARC), and thymus and activation-regulated chemokine (TARC) exclusively in the dermis started after 12 hours reaching maximum levels at 72 hours and was associated with infiltration of T cells into the epidermal compartment. Our data provide evidence that migrating effector cells encounter multiple chemoattractant signals in a complex spatial and temporal pattern. In particular, keratinocytes contribute to the vigorous immigration by sequential expression of MCP-1, RANTES, and interferon-inducible protein-10 (IP-10) monokine induced by gamma interferon (MIG), indicating that chemokine-mediated nonimmunological mechanisms precede and corroborate antigen-specific mechanisms during elicitation of contact hypersensitivity.

Allergens↗
PubMed2001

Chemokines in cutaneous wound healing.

Healing of wounds is one of the most complex biological events after birth as a result of the interplay of different tissue structures and a large number of resident and infiltrating cell types. The latter are mainly constituted by leukocyte subsets (neutrophils, macrophages, mast cells, and lymphocytes), which sequentially infiltrate the wound site and serve as immunological effector cells but also as sources of inflammatory and growth-promoting cytokines. Recent data demonstrate that recruitment of leukocyte subtypes is tightly regulated by chemokines. Moreover, the presence of chemokine receptors on resident cells (e.g., keratinocytes, endothelial cells) indicates that chemokines also contribute to the regulation of epithelialization, tissue remodeling, and angiogenesis. Thus, chemokines are in an exclusive position to integrate inflammatory events and reparative processes and are important modulators of human-skin wound healing. This review will focus preferentially on the role of chemokines during skin wound healing and intends to provide an update on the multiple functions of individual chemokines during the phases of wound repair.

Animals↗
PubMed2000

Ras-independent activation of the Raf/MEK/ERK pathway upon calcium-induced differentiation of keratinocytes.

MAPKs are crucially involved in the regulation of growth and differentiation of a variety of cells. To elucidate the role of MAPKs in keratinocyte differentiation, activation of ERK, JNK, and p38 in response to stimulation with extracellular calcium was analyzed. We provide evidence that calcium-induced differentiation of keratinocytes is associated with rapid and transient activation of the Raf/MEK/ERK pathway. Stimulation of keratinocytes with extracellular calcium resulted in activation of Raf isozymes and their downstream effector ERK within 10-15 min, but did not increase JNK or p38 activity. Calcium-induced ERK activation differed in kinetics from mitogenic ERK activation by epidermal growth factor and could be modulated by alterations of intracellular calcium levels. Interestingly, calcium stimulation led to down-regulation of Ras activity at the same time that ERK activation was initiated. Expression of a dominant-negative mutant of Ras also did not significantly impair calcium-induced ERK activation, indicating that calcium-mediated ERK activation does not require active Ras. Despite the transient nature of ERK activation, calcium-induced expression of the cyclin-dependent kinase inhibitor p21/Cip1 and the differentiation marker involucrin was sensitive to MEK inhibition, which suggests a role for the Raf/MEK/ERK pathway in early stages of keratinocyte differentiation.

Animals↗
PubMed2000

Rho proteins and the p38-MAPK pathway are important mediators for LPS-induced interleukin-8 expression in human endothelial cells.

Bacterial endotoxin (lipopolysaccharide, or LPS) has potent proinflammatory properties by acting on many cell types, including endothelial cells. Secretion of the CXC-chemokine interleukin-8 (IL-8) by LPS-activated endothelial cells contributes substantially to the inflammatory response. Using human umbilical vein endothelial cells (HUVECs), we analyzed the role of small GTP-binding Rho proteins and p38 mitogen-activated protein kinase (MAPK) for LPS-dependent IL-8 expression in endothelial cells. Specific inactivation of RhoA/Cdc42/Rac1 by Clostridium difficile toxin B-10463 (TcdB-10463) reduced LPS-induced tyrosine phosphorylation, nuclear factor (NF)-kappaB-dependent gene expression, IL-8 messenger RNA, and IL-8 protein accumulation but showed no effect on LPS-dependent p38 MAPK activation. Inhibition of p38 MAPK by SB 202190 also blocked LPS-induced NF-kappaB activation and IL-8 synthesis. Furthermore, selective activation of the p38 MAPK pathway by transient expression of a constitutively active form of MAPK kinase (MKK)6, the upstream activator of p38, was as effective as LPS with respect to IL-8 expression in HUVECs. In summary, our data suggest that LPS-induced NF-kappaB activation and IL-8 synthesis in HUVECs are regulated by both a Rho-dependent signaling pathway and the MKK6/p38 kinase cascade.

Cells, Cultured↗
PubMed2000

[Subepidermal bullous autoimmune dermatosis with linear deposition of IgA amd IgG].

A 29-year-old female patient with an autoimmune subepidermal blistering disease had linear deposits of both IgA and IgG at the basement membrane zone. Clinically, the patient presented with tense blisters on the face, trunk, extremities and oral mucosa. Histologically, we found a subepidermal blister formation and a predominantly neutrophilic infiltrate. Direct immunofluorescence showed linear deposits of IgA along the basement membrane zone, as well as linear deposits of IgG and C3 as typically found in bullous pemphigoid. Indirect immunofluorescence demonstrated circulating IgA and IgG autoantibodies. This case extends previous reports on a subgroup of patients with subepidermal blistering diseases characterized by the presence of both IgA and IgG anti-basement membrane antibodies. These patients reveal clinical, histological and immunopathological features of linear IgA disease and bullous pemphigoid.

Adult↗